Evolution of peptidoglycan biosynthesis under the selective pressure of antibiotics in Gram-positive bacteria

Authors

  • Jean-Luc Mainardi,

    1. INSERM, U872, LRMA, Centre de Recherche des Cordeliers, Paris, France
    2. Université Pierre et Marie Curie – Paris 6, UMR 872, Paris, France
    3. Université Paris Descartes, UMR 872, Paris, France
    4. AP-HP, Hôpital Européen Georges Pompidou, Paris, France
    Search for more papers by this author
  • Régis Villet,

    1. INSERM, U872, LRMA, Centre de Recherche des Cordeliers, Paris, France
    2. Université Pierre et Marie Curie – Paris 6, UMR 872, Paris, France
    3. Université Paris Descartes, UMR 872, Paris, France
    Search for more papers by this author
  • Timothy D. Bugg,

    1. Department of Chemistry, University of Warwick, Coventry, UK
    Search for more papers by this author
  • Claudine Mayer,

    1. INSERM, U872, LRMA, Centre de Recherche des Cordeliers, Paris, France
    2. Université Pierre et Marie Curie – Paris 6, UMR 872, Paris, France
    3. Université Paris Descartes, UMR 872, Paris, France
    Search for more papers by this author
  • Michel Arthur

    1. INSERM, U872, LRMA, Centre de Recherche des Cordeliers, Paris, France
    2. Université Pierre et Marie Curie – Paris 6, UMR 872, Paris, France
    3. Université Paris Descartes, UMR 872, Paris, France
    Search for more papers by this author

  • Editor: Arie van der Ende

Correspondence: Michel Arthur, LRMA, Centre de Recherche des Cordeliers, UMRS 872 – Pôle 4 – Equipe 12 (ex U655), INSERM–Université Pierre et Marie Curie – Université Paris Descartes, 15, rue de l'Ecole de Médecine, 75270 Paris Cedex 06, France. Tel.: +33 1 43 25 00 33; fax: +33 1 43 25 68 12; e-mail: michel.arthur@bhdc.jussieu.fr

Abstract

Acquisition of resistance to the two classes of antibiotics therapeutically used against Gram-positive bacteria, the glycopeptides and the β-lactams, has revealed an unexpected flexibility in the peptidoglycan assembly pathway. Glycopeptides select for diversification of the fifth position of stem pentapeptides because replacement of d-Ala by d-lactate or d-Ser at this position prevents binding of the drugs to peptidoglycan precursors. The substitution is generally well tolerated by the classical d,d-transpeptidases belonging to the penicillin-binding protein family, except by low-affinity enzymes. Total elimination of the fifth residue by a d,d-carboxypeptidase requires a novel cross-linking enzyme able to process the resulting tetrapeptide stems. This enzyme, an l,d-transpeptidase, confers cross-resistance to β-lactams and glycopeptides. Diversification of the side chain of the precursors, presumably in response to the selective pressure of peptidoglycan endopeptidases, is controlled by aminoacyl transferases of the Fem family that redirect specific aminoacyl-tRNAs from translation to peptidoglycan synthesis. Diversification of the side chains has been accompanied by a parallel divergent evolution of the substrate specificity of the l,d-transpeptidases, in contrast to the d,d-transpeptidases, which display an unexpected broad specificity. This review focuses on the role of antibiotics in selecting or counter-selecting diversification of the structure of peptidoglycan precursors and their mode of polymerization.

Ancillary